# Proton pump inhibitor use and pancreatic risk: evidence from the UK biobank participants and animal experiments

## TL;DR

This study finds no strong evidence that regular use of proton pump inhibitors increases the risk of pancreatic diseases, based on data from over 489,000 people and animal experiments.

## Contribution

The study combines large-scale human data with experimental validation to assess the pancreatic risks of PPIs comprehensively.

## Key findings

- Regular PPI use showed a time-dependent but unstable association with acute pancreatitis.
- Experimental validation in mice found no effect of PPIs on pancreatic inflammation or damage.
- Findings suggest PPIs do not significantly influence the risk of acute or chronic pancreatitis or pancreatic cancer.

## Abstract

Proton pump inhibitors (PPIs) are widely prescribed for gastrointestinal disorders and are often used empirically in patients with pancreatic disease, yet their long-term impact on pancreatic health remains unclear. We evaluated whether regular PPI use is associated with risks of acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC).

We analyzed 489,394 UK Biobank participants aged 38–73 years, comparing regular PPI users with non-users and with histamine-2 receptor antagonist (H2RA) users as an active comparator. Associations with incident pancreatic outcomes were estimated using Cox regression models, landmark analysis, and propensity score matching, supplemented by multiple sensitivity analyses, including stratified/interaction analyses, E-values, time-varying exposure models with immortal-time correction, dfbeta residuals correction, stricter follow-up with Firth penalization, full-cohort multivariable modeling, and alternative matching (disease risk score 1:1, entropy balancing). Complementary in vivo experiments used a cerulein-induced acute pancreatitis mouse model to examine the effects of short- and long-term PPI administration on pancreatic inflammation and histopathology.

In primary analyses, regular PPI use showed a time-dependent association with acute pancreatitis. However, this association was not robust: multiple sensitivity analyses indicated instability of the finding. Experimental validation in mice demonstrated that neither short-term nor long-term PPI administration altered pancreatic inflammation or histopathological damage in the cerulein-induced model.

Integrating large-scale cohort data with experimental evidence, our findings suggest that regular PPI use does not meaningfully influence the risk of acute pancreatitis, chronic pancreatitis, or pancreatic cancer.